1. Field of the Invention
The use of liposomes as carriers for introducing drugs and macromolecules into cells has been reported. Liposomes are vesicles comprising a phospholipid bilayer enclosing an aqueous or partially aqueous volume produced by hydration and mechanical dispersion of lipid material in an aqueous medium. Drugs may be introduced into the aqueous volume by suspension or dissolution in the aqueous medium. It is believed that liposome-encapsulated drugs are transported essentially intact to targeted tissues and organs in the body, where they are transferred into individual cells and released. Advantages of liposome encapsulation lies in the protection of the drug while it is delivered to the organ or tissue, the liposome-mediated transport of the drug into the cell at an elevated localized concentration, and protection of the untargeted cells from the drug.
Scar tissue results from the formation of a hard layer of connective tissue formed over a healing wound or cut. In many cases, scar tissue results in tissue contraction which may result in disfiguration and, more seriously, which may produce side effects which comprise tissue and organ function. Scar tissue formation in the eye, referred to as proliferative vitreoretinopathy, frequently results in retinal detachment. Current methods for preventing such scar tissue formation in the eye, such as corticosteroids, are not always effective. Other examples of scar tissue formation which are detrimental include posterior tear capsule opacification after cataract surgery, scar tissue over filtration sites for glaucoma, scar tissue formation after skin grafting, and scar tissue formation around breast implants. All of these might benefit from fluoroorotate therapy.
It would be desirable to provide improved methods and compositions for inhibiting the formation of scar tissue under a variety of circumstances and particularly the formation of scar tissue in the eye. It is of substantial importance to be able to inhibit scar tissue without adversely affecting cells and cell processes.
2. Description of the Relevant Literature
5-Fluoroorotate is a derivative of 5-fluorouracil for which no cellular transport system exists. Bosch et al. (1958) Cancer Res. 18:335-343. Both 5-fluorouracil and 5-fluoroorotate interfere with ribosomal maturation (Wilkinson et al. (1971) J. Biol. Chem. 246:63-68 and J. Biol. Chem. 246:6418-6427) and may also be metabolized to fluorodeoxyuridine monophosphate, an inhibitor of thymidylate synthetase (Hartman and Heidelberger (1961) J. Biol. Chem. 236:3006-3013). Attempts to encapsulate 5-fluorouracil in liposomes have met with limited success. Gregoriadis et al. (1974) Lancet 1:1313-1316 and Gregoriadis (1974) Biochem. Soc. Trans. 2:117. Heath et al., ARAVO Abstracts, p. 284, 8-10:15, May 10, 1985, report advantages of encapsulating 5-fluoroorotate for treatment of retinal detachment.